ERα/ERβ-directed CBS transcription mediates E2β-stimulated hUAEC H2S production

in Journal of Molecular Endocrinology
Authors:
Jin Bai Department of Obstetrics and Gynecology, University of California, Irvine, California, USA

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Thomas J Lechuga Department of Biology, San Bernardino Valley College, San Bernardino, California, USA

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Joshua Makhoul Department of Obstetrics and Gynecology, University of California, Irvine, California, USA

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Hao Yan Department of Obstetrics and Gynecology, University of California, Irvine, California, USA

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Carol Major Department of Obstetrics and Gynecology, University of California, Irvine, California, USA

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Afshan Hameed Department of Obstetrics and Gynecology, University of California, Irvine, California, USA

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Dong-bao Chen Department of Obstetrics and Gynecology, University of California, Irvine, California, USA

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https://orcid.org/0000-0002-1067-6018

Correspondence should be addressed to D Chen: dongbaoc@uci.edu
DOI:
https://doi.org/10.1530/JME-22-0175
Volume/Issue:
Volume 70: Issue 2
Article Type:
Research Article
Article ID:
e220175
Online Publication Date:
09 Jan 2023
Copyright:
© Society for Endocrinology 2023
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Elevated endogenous estrogens stimulate human uterine artery endothelial cell (hUAEC) hydrogen sulfide (H2S) production by selectively upregulating the expression of H2S synthesizing enzyme cystathionine β-synthase (CBS), but the underlying mechanisms are underdetermined. We hypothesized that CBS transcription mediates estrogen-stimulated pregnancy-dependent hUAEC H2S production. Estradiol-17β (E2β) stimulated CBS but not cystathionine γ-lyase (CSE) expression in pregnant human uterine artery ex vivo, which was attenuated by the estrogen receptor (ER) antagonist ICI 182,780. E2β stimulated CBS mRNA/protein and H2S production in primary hUAEC from nonpregnant and pregnant women, but with greater responses in pregnant state; all were blocked by ICI 182,780. Human CBS promoter contains multiple estrogen-responsive elements (EREs), including one ERE preferentially binding ERα (αERE) and three EREs preferentially binding ERβ (βERE), and one full ERE (α/βERE) and one half ERE (½α/βERE) binding both ERα and ERβ. Luciferase assays using reporter genes driven by human CBS promoter with a series of 5′-deletions identified the α/βEREs binding both ERα and ERβ (α/βERE and ½α/βERE) to be important for baseline and E2β-stimulated CBS promoter activation. E2β stimulated ERα/ERβ heterodimerization by recruiting ERα to α/βEREs and βERE, and ERβ to βERE, α/βEREs, and αERE. ERα or ERβ agonist alone trans-activated CBS promoter, stimulated CBS mRNA/protein and H2S production to levels comparable to that of E2β-stimulated, while ERα or ERβ antagonist alone abrogated E2β-stimulated responses. E2β did not change human CSE promoter activity and CSE mRNA/protein in hUAEC. Altogether, estrogen-stimulated pregnancy-dependent hUAEC H2S production occurs by selectively upregulating CBS expression via ERα/ERβ-directed gene transcription.

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Online ISSN:
1479-6813
Print ISSN:
0952-5041
Copyright:
© Society for Endocrinology 2023
Article ID:
e220175
Article Type:
Research Article
Received Date:
29 Nov 2022
Accepted Date:
06 Dec 2022
Print Publication Date:
01 Feb 2023
Online Publication Date:
09 Jan 2023
Keywords:
estrogens; estrogen receptor; H2S biosynthesis; CBS transcription; pregnancy

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